Data from human studies and experimental animal models strongly implicate Th2-derived cytokines as contributing to atopic asthma, with interleukin-4 (IL-4) and interleukin-13 (IL-13; see, e.g., Minty et al., 1993 Nature 362:248-250; McKenzie et al., 1993 Proc. Natl. Acad. Sci. USA 90:3735-3739; Acc. Nos: U31120 and L13029 (human) and NM 001032929 (Macaca mulatta)) playing the most central role. These two cytokines have significant structural similarities and share certain receptor components. The receptor that IL-4 and IL-13 share is a dual IL-4R/IL-13 receptor (or type II receptor) which binds both IL-4 and IL-13. This receptor is composed of the IL-4Rα chain (see, e.g., Idzerda et al., 1990 J. Exp. Med. 171:861-873) and the IL-13Rα1 chain (see, e.g., Hilton et al., 1996 Proc. Natl. Acad. Sci. USA 93:497-501; Aman et al., 1996 J. Biol. Chem. 271:29265-29270; Miloux et al., 1997 FEBS Lett. 401:163-166; Acc. Nos: U62858 and CAA70508 (human) and AAP78901 (Macaca fascicularis)). The dual IL-4R/IL-13R receptor is expressed on hematopoietic and non-hematopoietic cells, including lung epithelial and smooth muscle cells. Both IL-4 and IL-13, additionally, each have one receptor that recognizes them to the exclusion of the other. For instance, IL-4 receptor (IL-4R) type I, composed of the IL-4Rα chain and the common gamma chain (γc), specifically binds IL-4. IL-4R type I is expressed exclusively on cells of hematopoietic origin. The receptor specific for IL-13, IL-13Rα2, binds IL-13 with high affinity, but apparently does not transduce signals. Rather, the receptor acts as a decoy to attenuate the response to IL-13.
IL-13 and IL-4 carry out a number of functions and both regulate a number of functions related to the allergic phenotype, such as isotype class switching to IgE in B-cells, activation of mast cells and eosinophils, up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, and production of chemokines such as eotaxins, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC).
IL-4 and IL-13, though, have many distinct functions in vitro and in vivo owing to differences in their receptor complexes. For instance, sequestration of IL-13, but not IL-4, has been shown to prevent airway hyperreactivity and reduce mucous production in mouse asthma models. This correlation between IL-13 and the asthmatic response has been further supported by other studies; see, e.g., Hershey et al., 2003 J. Allergy Clin. Immunol. 111(4):677-690; Grunig et al., 1998 Science 282(5397):2261-2263; Mattes et al., 2001 J. Immunol. 167(3):1683-1692; and Fulkerson et al., 2006 Am. J. Respir. Cell. Mol. Biol. 35(3) 337-346. Delivery of IL-13 to the lung, for example, has been found to be sufficient to induce the entire asthma-like phenotype in mice. Treated animals develop airway hyperreactivity, eosinophil-rich cell inflammation, goblet cell hyperplasia with associated mucous overproduction, and subepithelial fibrosis; see, e.g., Wills-Karp et al., 1998 Science 282(5397): 2258-2261; Reiman et al., 2006 Infect. Immun. 74(3): 1471-1479; and Kaviratne et al., 2004 J. Immunol. 173(6):4020-4029. Expression of IL-13 has, furthermore, been reported to be elevated in the lungs of human asthmatics. In addition, several groups have reported associations of polymorphisms in the IL-13 gene with an increased risk of allergic traits and asthma symptoms. Some of these polymorphisms have been shown to be correlated with increased expression of IL-13; see, e.g., Huang et al., 1995 J. Immunol. 155(5) 2688-2694; Naseer et al., 1997 Am. J. Respir. Crit. Care Med. 155(3):845-851; Vladich et al., 2005 J. Clin. Invest. 115(3):747-754; Chen et al., 2004 J. Allergy Clin. Immunol. 114(3):553-560; and Vercelli et al., 2002 Curr. Opin. Allergy Clin. Immunol. 2(5):389-393.
IL-13 has also been associated with various other conditions, including but not limited to various respiratory and allergy-mediated disorders, fibrosis, scleroderma, inflammatory bowel disease and certain cancers; see, e.g., Wynn, T. A., 2003 Annu. Rev. Immunol. 21:425-456; Terabe et al., 2000 Nat. Immunol. 1(6):515-520; Fuss et al., 2004 J. Clin. Invest. 113(10):1490-1497; Simms et al., 2002 Curr. Opin. Rheumatol. 14(6):717-722; and Hasegawa et al., 1997 J. Rheumatol. 24(2):328-332.
An antagonist of IL-13 would, therefore, be a highly attractive molecule for use in the development of a treatment for IL-13-associated disorders. An effective antibody antagonist would interfere with the binding of IL-13 to IL-13R. An effective antibody antagonist to IL-13Rα1 may also interfere with the binding of IL-13 and prevent heterodimerization of IL-4Rα and IL-13Rα1. Such an antibody could inhibit signaling of both IL-13 and IL-4 through the type II receptor while sparing IL-4 signaling through the type I receptor. Signaling through the type I receptor is essential in the induction phase of the immune response during which Th2 cells differentiate. T cells do not express IL-13Rα1 so the type II receptor plays no role in Th2 differentiation. Hence, an IL-13Rα1 antibody should not affect the overall Th1/Th2 balance. Signaling through the type II IL-4/IL-13 receptor is critical during the effector stage of the immune response during established allergic inflammation. Thus, blockade of the type II receptor should have a beneficial effect on many of the symptoms of asthma and other IL-13R-mediated conditions and should, therefore, be an effective disease modifying agent.
Antibodies against IL-13Rα1 (both monoclonal and polyclonal) have been described in the art; see, e.g., WO 97/15663, WO 03/80675; WO 03/46009; WO 06/072564; Gauchat et al., 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et al., 2000 Eur. J. Immunol. 30:3157-3164; Clement et al., 1997 Cytokine 9(11):959 (Meeting Abstract); Ogata et al., 1998 J. Biol. Chem. 273:9864-9871; Graber et al., 1998 Eur. J. Immunol. 28:4286-4298; C. Vermot-Desroches et al., 2000 Tissue Antigens 5(Supp. 1):52-53 (Meeting Abstract); Poudrier et al., 2000 Eur. J. Immunol. 30:3157-3164; Akaiwa et al., 2001 Cytokine 13:75-84; Cancino-Diaz et al., 2002 J. Invest. Dermatol. 119:1114-1120; and Krause et al., 2006 Mol. Immunol. 43:1799-1807.
There is a need for an antibody with enhanced biological activity that could impact activities associated with the allergy and asthmatic response as well as other various conditions that have been attributed at least in part to an increased expression/functioning of IL-13Rα1. There is further a need for an antibody molecule with high affinity for IL-13Rα1 with low immunogenicity in humans. Accordingly, it would be of great import to produce a therapeutic-based human antibody antagonist of IL-13Rα1 that inhibits or antagonizes the activity of IL-13Rα1 and the corresponding role IL-13Rα1 plays in various therapeutic conditions.